T cells, and, in particular CD8+ cytotoxic T cells (CTLs) are important effector cells in anti-viral and anti-cancer immunity, and these cells are promising candidates for adoptive immunotherapy of cancer. It is the ultimate goals of our studies to reveal the cellular and molecular requirements for CTL differentiation and effector functions. This knowledge is needed for the development of novel strategies and drugs for immunomodulation. The exquisite specificity toward antigen-bearing cells (cognate targets) is one of the most important properties of CD8+ CTL- mediated cytotoxicity. However, we found that in the presence of antigen-bearing targets the CTLs acquire the ability to efficiently lyse noncognate target cells ("innocent bystanders") by a Fas ligand (FasL)/Fas-based cytotoxicity mechanism. The lysis of bystanders is tightly regulated by the adhesion molecule LFA-1 on the surface of the activated, by ICAM-1 molecules on bystanders and it is minimized by the activity of constitutively active and cell surface membrane-associated PP2a protein phosphatase in CTL. The TCR is not the only activator of FasL- mediated cytoxicity, since Thy-1 surface antigens are also able to induce the lysis of Fas-expressing targets by different T cells. In our recent and ongoing studies we focused on evaluation of mechanisms of non-TCR-induced (anti-Thy-1 mAb) as compared to TCR-induced bystander lysis and were developing reagents to ask questions about the role of individual molecules PP2a phosphatase and LFA-1/ICAM-1 interactions in mechanisms of triggering and termination of lysis of bystanders by CTL. It is shown, that LFA-1/ICAM-1 interactions are required for destruction of bystander target cells but not for the lysis of antigen-expressing targets, raising the questions about the role of ICAM-1 in generation of CTL. Experiments indicate that molecules of ICAM-1 on stimulators are not needed to directly prime CD8 T-cells but are, however, required to prime or activate CD4 T-cells to produce cytokines which are needed for expansion and/or survival of CD8 T-cells to expand and/or survive. We propose that the lysis of bystanders represents an acceptable level of "collateral" damage to Fas-expressing bystanders during normal immune response, but the persistent presence of activated CTLs could result in immunopathologies involving such tissues as heart and liver. The evaluation of signals that trigger and control this bystander?s lysis by CTL may help in diagnosis and prevention of infection-related immunopathologies of heart and liver. These findings may help to clarify mechanisms of graft rejection and some immune diseases.